E. Negishi, A. O. King and N. Okukado, J. Org. Chem. 42, 1821 (1977), disclosed that the cross-coupling of aryl- and benzylzinc derivatives with aryl bromides or iodides in the presence of catalytic amounts of a Ni or Pd catalyst provided a general and highly chemo- and regioselective synthetic route to unsymetrical biaryls and diarylmethanes, with the amounts of the homocoupled biaryls being less than five percent. J. W. Tilley, J. W. Clader, S. Zawoiski, M. Wirkus, R. A. LeMahieu, M. O'Donnell, H. Crowley & A. F. Welton; J. Med. Chem. 32, 1814 (1989), show an example of a Negishi cross-coupling in Scheme II on page 1816 and in the Experimental Section in column 2, page 1818, second example in which 2-bromo-3',4'-dimethoxy-1,1'-biphenyl-4-carboxylic acid methyl ester is prepared. In this example the 3,4-dimethoxyphenylzinc reactant is made by reacting butyllithium with 3,4-dimethoxybrombenzene, followed by transmetallation with zinc chloride. The cross-coupling catalyst is bis(triphenylphoshine)palladium dichloride. A. S. Bell, D. A. Roberts & K. S. Ruddock; Synthesis 843 (1987), report the direct synthesis of 6-pyridinyl-2(1H)-quinolinones by palladium-catalyzed cross-coupling of pyridinylzinc chlorides with haloquinolinones. The pyridinylzinc chloride reagents are obtained by transmetallation of pyridinyllithium or pyridinylmagnesium halides with zinc chloride.
U.S. Pat. No. 5,039,814 (Merck & Co.) describes the production of ortho-lithiated aryltetrazoles of structure ##STR1## Such ortho-lithiated tetrazole is either treated with an electrophile or with a metal halide M(L)n to give a transmetallated compound (M.dbd.Zn, Mg, Cu, B, Al or Cd). The latter is then treated with aryl halides in presence of catalyst (palladium or nickel) to yield biphenyl compounds of structure ##STR2##
In contrast, the process disclosed herein utilizes a Grignard reaction with, for example, a 1-(t-butyl)-3-(2-bromophenyl)tetrazole to produce the t-butylphenyltetrazole-2-magnesium bromide Grignard reagent rather than such ortho-lithiated reactant A which is then transmetallized with zinc chloride. The process disclosed herein therefore avoids the use of pyrophoric butyllithium.
Steps 3, 4 and 5 of Example 3 of the said U.S. Pat. No. 5,149,699 (American Home Product Corporation) discloses the preparation of the subject intermediate, {also known as 2,4-Dimethyl-5,6,8-trihydro-8-[[2'-(1-tert-butyl-1H-tetrazol-5-yl)[1,1-bip henyl]-4-yl]methyl]-7H-pyrido[2,3-d]pyrimidin-7-one, } by the following reaction sequence: ##STR3## As seen from the above schematic, the 2-t-butyl-5-bromophenyl-2H-tetrazole, referred to hereinafter as "t-butylbromotetrazole", (1) is reacted with magnesium to produce the corresponding Grignard reagent which is then further reacted to produce the boronic acid (2). The overall yield for these step is 48%. The palladium catalyzed cross-coupling of the boronic acid (2) and the 8-[(4-bromophenyl)-methyl]5,8-dihydro-2,4-dimethyl-pyrido[2,3-d]pyrimidin- 7(6H)-one, referred to hereinafter as "bromobenzyl lactam", (3) afford the subject intermediate in 66% yield. The process disclosed herein surprisingly provides better yields and avoids the isolation of the boronic acid (2).
Example 5 of the European patent EP 0550313A1 (Synthelabo) describes the preparation of the biphenyl product (5) by the following sequence. ##STR4## The aryl bromide (4) is converted to an organozinc which is used in the cross-coupling reaction to afford the biphenyl product (5) in yield ranging from 60 to 80%. In the process disclosed herein, the Grignard reagent is prepared from the aryltetrazole. This is an advantage since the arylhalide which does not contain the tetrazole ring can be fully functionalized.
Scheme IX of EP 0497150 A1 (American Cyanamid Company), shown below, shows a palladium or nickel catalyzed coupling of a 5-(2-M-phenyl)-1-(triphenylmethyl)-1H-tetrazole (108) with a 3-[4-(R.sup.40 -phenyl)methyl]-quinazolinone (109); where M is selected from --MgBr, --Sn(loweralkyl of 1-4 carbon atoms or phenyl), Li or --Zn complex, and R.sup.40 is selected from I, Br, or OSO.sub.2 CF.sub.3. The only specific illustration of this reaction is in Example 90 where M is --MgBr and R.sup.40 is bromo, that is, the tetrazole reactant is 5-(2-bromophenyl)-1-(triphenylmethyl)-1H-tetrazole, and the quinazolinone reactant is 3-[4-bromophenyl)methyl]-2-butyl -6-(1-methoxy-1-methylethyl)-4(3H)-quinazolinone]. ##STR5##